Aza-indoles and related compounds having sphingosine-1-phosphate (s1p) receptor antagonist biological activity

ABSTRACT

The present invention provides compounds are disclosed herein having the formula: 
     
       
         
         
             
             
         
       
         
         
           
             Wherein n is 1 or 2; m is 0 or 1; p is 0, 1 or 2; R 1  is aryl, heteroaryl or alkyl; 
             R 2  is C 1-6  hydrocarbyl, alkylacyl or hydroxyalkyl; R 3  is aryl, heteroaryl, or alkyl; R 4  is H, OH, —O—(C 1-6  alkyl), —NH—(C 1-6  alkyl), or oxide; 
             R 5  is H, halogen, C 1-6  alkyl, O—(C 1-6  alkyl), aryl, heteroaryl, —C(═O)(C 1-6  alkyl), substituted or un-substituted oxazolin-2-yl; 
             X=O, NH, —C(═O)— or —N═CH—; and 
             Each L is independently alkylene and carbonyl.
 
Therapeutic methods, compositions, and medicaments related thereto are also disclosed

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Divisional of U.S. patent application Ser. No.12/493,463, filed Jun. 29, 2009, which claims priority under 35 U.S.C.§120 to U.S. Provisional Patent Application No. 61/133,648 filed on Jun.30, 2008, each of which is incorporated herein by reference in itsentirety.

BACKGROUND

Sphingosine is a compound having the chemical structure shown in thegeneral formula described below, in which Y¹ is hydrogen. It is knownthat various sphingolipids, having sphingosine as a constituent, arewidely distributed in the living body including on the surface of cellmembranes of cells in the nervous system.

A sphingolipid is one of the lipids having important roles in the livingbody. A disease called lipidosis is caused by accumulation of aspecified sphingolipid in the body. Sphingolipids present on cellmembranes function to regulate cell growth; participate in thedevelopment and differentiation of cells; function in nerves; areinvolved in the infection and malignancy of cells; etc. Many of thephysiological roles of sphingolipids remain to be solved. Recently thepossibility that ceramide, a derivative of sphingosine, has an importantrole in the mechanism of cell signal transduction has been indicated,and studies about its effect on apoptosis and cell cycle have beenreported.

Sphingosine-1-phosphate is an important cellular metabolite, derivedfrom ceramide that is synthesized de novo or as part of thesphingomeyeline cycle (in animals cells). It has also been found ininsects, yeasts and plants.

The enzyme, ceramidase, acts upon ceramides to release sphingosine,which is phosphorylated by sphingosine kinase, a ubiquitous enzyme inthe cytosol and endoplasmic reticulum, to form sphingosine-1-phosphate.The reverse reaction can occur also by the action of sphingosinephosphatases, and the enzymes act in concert to control the cellularconcentrations of the metabolite, which concentrations are always low.In plasma, such concentration can reach 0.2 to 0.9 μM, and themetabolite is found in association with the lipoproteins, especially theHDL. It should also be noted that sphingosine-1-phosphate formation isan essential step in the catabolism of sphingoid bases.

Like its precursors, sphingosine-1-phosphate is a potent messengermolecule that perhaps uniquely operates both intra- andinter-cellularly, but with very different functions from ceramides andsphingosine. The balance between these various sphingolipid metabolitesmay be important for health. For example, within the cell,sphingosine-1-phosphate promotes cellular division (mitosis) as opposedto cell death (apoptosis), which it inhibits. Intracellularly, it alsofunctions to regulate calcium mobilization and cell growth in responseto a variety of extracellular stimuli. Current opinion appears tosuggest that the balance between sphingosine-1-phosphate and ceramideand/or sphingosine levels in cells is critical for their viability. Incommon with the lysophospholipids, especially lysophosphatidic acid,with which it has some structural similarities, sphingosine-1-phosphateexerts many of its extra-cellular effects through interaction with fivespecific G protein-coupled receptors on cell surfaces. These areimportant for the growth of new blood vessels, vascular maturation,cardiac development and immunity, and for directed cell movement.

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular disease.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

Fungi and plants have sphingolipids and the major sphingosine containedin these organisms has the formula described below. It is known thatthese lipids have important roles in the cell growth of fungi andplants, but details of the roles remain to be solved.

Recently it has been known that derivatives of sphingolipids and theirrelated compounds exhibit a variety of biological activities throughinhibition or stimulation of the metabolism pathways. These compoundsinclude inhibitors of protein kinase C, inducers of apoptosis,immuno-suppressive compounds, antifungal compounds, and the like.Substances having these biological activities are expected to be usefulcompounds for various diseases.

DESCRIPTION OF THE INVENTION

Compounds are disclosed herein having the formula:

Wherein n is 1 or 2 and indicates the number of enchained nitrogen atomsin the condensed 6 member ring; m is 0 or 1; p is 0, 1 or 2; R₁ is aryl,heteroaryl or alkyl;R₂ is selected from the group consisting of C₁₋₆ hydrocarbyl, alkylacyland hydroxyalkyl;R₃ is selected from the group consisting of aryl, heteroaryl, or alkyl;R₄ is H, OH, —O—(C₁₋₆ alkyl), —NH—(C₁₋₆ alkyl), and oxide;R₅ is selected from the group consisting of H, halogen, C₁₋₆ alkyl,O—(C₁₋₆ alkyl), aryl, heteroaryl, —C(═O)(C₁₋₆ alkyl), substituted andun-substituted oxazolin-2-yl;X is selected from the group consisting of O, NH, —C(═O)— and —N═CH—;andL is selected from the group consisting of alkylene, and carbonyl.

Within the scope of the above general formula, preferably the condensedaza-indole ring moeity is selected from the group of ring systems setforth below:

The preferred R₁-R₅ groups are as follows:

-   -   R₅: various groups exemplified below in specific examples

R₅ is selected from the group consisting of lower alkyl, e.g. C₁-C₆alkyl, i.e. isopropyl, n-butyl, etc. cycloalkyl, e.g. cyclopentyl;thiazolyl; oxazolyl; oxadiazolyl; pyridinyl, oxazolin-2-yl, etc. X isselected from the group consisting of O, C(O), NH, etc. or X is notpresent.

Specific Examples that illustrate various combinations of R₄ andR₅—X_(m) include:

These compounds are useful for the treatment of diseases or conditionssuch as glaucoma, dry eye, angiogenesis, cardiovascular conditions anddiseases, wounds, and pain. The compound is incorporated into a dosageform or a medicament and administered to the mammal, such as a person,in need thereof. Different types of suitable dosage forms andmedicaments are well known in the art, and can be readily adapted fordelivery of the compounds disclosed herein.

Thus, one embodiment is a method of treating a disease or conditioncomprising administering a compound disclosed herein to a mammal in needthereof, said disease or condition being selected from: glaucoma, dryeye, angiogenesis, cardiovascular conditions and diseases, wounds, andpain.

Another embodiment is use of a compound disclosed herein in themanufacture of a medicament for the treatment of a disease or conditionin a mammal, said disease or condition being selected from: glaucoma,dry eye, angiogenesis, cardiovascular conditions and diseases, wounds,and pain.

For the purposes of this disclosure, “treat,” “treating,” or “treatment”refer to the use of a compound, composition, therapeutically activeagent, or drug in the diagnosis, cure, mitigation, treatment, orprevention of disease or other undesirable condition.

Stable means that a compound is sufficiently stable to be stored in abottle at room temperature under a normal atmosphere for at least 12hours, or stable enough to be useful for any purpose disclosed herein.

Unless otherwise indicated, reference to a compound should be construedbroadly to include pharmaceutically acceptable salts, prodrugs,tautomers, alternate solid forms, non-covalent complexes, andcombinations thereof, of a chemical entity of the depicted structure orchemical name.

A pharmaceutically acceptable salt is any salt of the parent compoundthat is suitable for administration to an animal or human. Apharmaceutically acceptable salt also refers to any salt which may formin vivo as a result of administration of an acid, another salt, or aprodrug which is converted into an acid or salt. A salt comprises one ormore ionic forms of the compound, such as a conjugate acid or base,associated with one or more corresponding counter-ions. Salts can formfrom or incorporate one or more deprotonated acidic groups (e.g.carboxylic acids), one or more protonated basic groups (e.g. amines), orboth (e.g. zwitterions).

A prodrug is a compound which is converted to a therapeutically activecompound after administration. For example, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Prodrug preparation is well known in the art. For example, “Prodrugs andDrug Delivery Systems,” which is a chapter in Richard B. Silverman,Organic Chemistry of Drug Design and Drug Action, 2d Ed., ElsevierAcademic Press: Amsterdam, 2004, pp. 496-557, provides further detail onthe subject.

Tautomers are isomers that are in rapid equilibrium with one another.For example, tautomers may be related by transfer of a proton, hydrogenatom, or hydride ion.

Unless stereochemistry is explicitly depicted, a structure is intendedto include every possible stereoisomer, both pure or in any possiblemixture.

Alternate solid forms are different solid forms than those that mayresult from practicing the procedures described herein. For example,alternate solid forms may be polymorphs, different kinds of amorphoussolid forms, glasses, and the like.

Non-covalent complexes are complexes that may form between the compoundand one or more additional chemical species that do not involve acovalent bonding interaction between the compound and the additionalchemical species. They may or may not have a specific ratio between thecompound and the additional chemical species. Examples might includesolvates, hydrates, charge transfer complexes, and the like.

Hydrocarbyl is a moiety consisting of carbon and hydrogen, including,but not limited to:

a. alkyl, which is hydrocarbyl that contains no double or triple bonds,such as:

-   -   linear alkyl, e.g. methyl, ethyl, n-propyl, n-butyl, n-pentyl,        n-hexyl, etc.,    -   branched alkyl, e.g. iso-propyl, t-butyl and other branched        butyl isomers, branched pentyl isomers, etc.,    -   cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, etc.,    -   combinations of linear, branched, and/or cycloalkyl;        b. alkenyl, which is hydrocarbyl having 1 or more double bonds,        including linear, branched, or cycloalkenyl        c. alkynyl, which is hydrocarbyl having 1 or more triple bonds,        including linear, branched, or cycloalkynyl;        d. combinations of alkyl, alkenyl, and/or akynyl

C₁₋₆ hydrocarbyl is hydrocarbyl having 1, 2, 3, 4, 5, or 6 carbon atoms.

C₁₋₆ alkyl is alkyl having 1, 2, 3, 4, 5, or 6, carbon atoms such asmethyl, ethyl, propyl isomers, butyl isomers, pentyl isomer, and hexylisomers, etc.

Aryl is an aromatic ring or ring system such as phenyl, naphthyl,biphenyl, and the like. Heteroaryl is an aromatic ring or ring systemcontaining one or more O, N, or S heteroatoms. Both aryl and heteroarylmay be substituted or unsubstituted, and unless otherwise indicated,“aryl” and “heteroaryl” should be taken to mean “substituted orunsubstituted aryl” and “substituted or unsubstituted heteroaryl.”Similarly, unless otherwise indicated, any specific aryl or heteroarylring such as “phenyl,” “pyridinyl,” “thienyl,” “furyl,” etc., should betaken to mean “substituted or unsubstituted phenyl,” “substituted orunsubstituted pyridinyl,” “substituted or unsubstituted thienyl,”“substituted or unsubstituted furyl,” etc.

Examples of substituents may include the following, subject to theconstraints defined herein for that particular moiety or substituent:

A. Hydrocarbyl, including, but not limited to:a. alkyl, such as:

-   -   linear alkyl, e.g. methyl, ethyl, n-propyl, n-butyl, n-pentyl,        n-hexyl, etc.,    -   branched alkyl, e.g. iso-propyl, t-butyl and other branched        butyl isomers, branched pentyl isomers, etc.,    -   cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl, etc.,    -   combinations of linear, branched, and/or cycloalkyl;        b. alkenyl, which is hydrocarbyl having 1 or more double bonds,        including linear, branched, or cycloalkenyl        c. alkynyl, which is hydrocarbyl having 1 or more triple bonds,        including linear, branched, or cycloalkynyl;        d. combinations of alkyl, alkenyl, and/or akynyl        B. alkyl-CN, such as —CH₂—CN, —(CH₂)₂—CN; —(CH₂)₃—CN, and the        like;

C. Hydroxy, —OH

D. hydroxyalkyl, i.e. alkyl-OH, such as hydroxymethyl, hydroxyethyl, andthe like;E. ether substituents, including —O-alkyl, alkyl-O-alkyl, and the like;F. thioether substituents, including —S-alkyl, alkyl-S-alkyl, and thelike;G. amine substituents, including —NH₂, —NH-alkyl, —N-alkyl¹alkyl² (i.e.,alkyl¹ and alkyl² are the same or different, and both are attached toN), alkyl-NH₂, alkyl-NH-alkyl, alkyl-N-alkyl¹alkyl², and the like;H. aminoalkyl, meaning alkyl-amine, such as aminomethyl (—CH₂-amine),aminoethyl, and the like;I. ester substituents, including —CO₂-alkyl, —CO₂₋phenyl, etc.;J. other carbonyl substituents, including aldehydes; ketones, such asacyl, including, acetyl, propionyl, and benzoyl substituents arecontemplated;K. fluorocarbons or hydrofluorocarbons such as —CF₃, —CH₂CF₃, etc.; andL. other nitrogen containing substituents such as —CN and —NO₂,M. other sulfur containing substitutents such as sulfide, sulfonyl orsulfoxide;N. aryl;O. combinations of the above are also possible, subject to theconstraints defined;P. Alternatively, a substituent may be —F, —Cl, —Br, or —I.

When R₁, R₃, R₄ or R₅ is heteroaryl, the formula thereof, including boththe ring and any substituents, may beC₁₋₆H₀₋₁₁N₀₋₃O₀₋₂S₀₋₂F₀₋₁Cl₀₋₁Br₀₋₁. Thus, if R₁, R₃, R₄ or R₅ isheteroaryl, it consists of from 1 to 6 carbon atoms, from 0 to 11hydrogen atoms, from 0 to 3 nitrogen atoms, from 0 to 2 oxygen atoms,from 0 to 2 sulfur atoms, from 0 to 1 fluorine atoms, from 0 to 1chlorine atoms, and from 0 to 1 bromine atoms.

The structures below are examples of useful heteroaryl moieties for R₁,R₃, R₄ or R₅.

The structures below are examples of useful aryl moieties for R₁, R₃, R₄or R₅

EXPERIMENTAL

Example 1

N-(6-methoxypyridin-3-yl)pivalamide (Compound 1). To a solution of6-methoxy-pyridin-3-amine (Aldrich, 10.0 g, 77 mmol) in anhydrous CH₂Cl₂(100 ml) at 0° C. was added Et₃N (13.9 ml, 100.1 mmol) and a solution ofpivaloyl chloride (10.5 ml, 84.7 mmol) in CH₂Cl₂ (20 ml). The mixturewas stirred at 0° C. for 10 min and at room temperature for 2 h. Afterquenched with ice, the reaction was diluted with CH₂Cl₂, washed with 1MNaOH, brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by chromatography on silica gel (0→30% EtOAc-hexanes) toyield the title compound as orange solid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32 (s, 9H), 3.92 (s, 3H), 6.73(d, J=9.1 Hz, 1H), 7.23 (s, 1H), 7.91 (dd, J=8.9, 2.8 Hz, 1H), 8.13 (d,J=2.6 Hz, 1H).

Example 2

N-(4-iodo-6-methoxypyridin-3-yl)pivalamide (Compound 2). To a solutionof N-(6-methoxypyridin-3-yl)pivalamide (Compound 1, 7.4 g, 35.6 mmol) inanhydrous THF (200 ml) at −78° C. under argon was added t-BuLi (1.7 M inpentane, 52 ml, 89.0 mmol) slowly. After stirred at −78° C. for 1 h, asolution of I₂ (22.6 g, 89.0 mmol) in anhydrous THF (100 ml) at −78° C.was cannulated into the reaction over 20 min and the reaction wasstirred for 15 min at −78° C. The cooling bath was then removed and thereaction stirred for 30 min, quenched cautiously with ice, extractedwith CH₂Cl₂. The organic layer was dried over Na₂SO₄, and concentratedin vacuo. The residue was purified by chromatography on silica gel(0→30% EtOAc-hexanes) to yield the title compound.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H), 3.92 (s, 3H), 7.25(s, 1H), 7.38 (s, 1H), 8.71 (s, 1H).

Example 3

4-Iodo-6-methoxypyridin-3-amine (Compound 3). A solution ofN-(4-iodo-6-methoxypyridin-3-yl)pivalamide (Compound 2, 2.33 g, 7.0mmol) in 10% H₂SO₄ (70 ml) was heated to reflux at 120° C. for 5 h. Themixture was cooled to 0° C. and was quenched cautiously with solid NaOH(10 g), extracted with EtOAc (×2). The combined organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by chromatography on silica gel (0→30% EtOAc-hexanes) toyield the title compound as off-white solid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.72 (s, 2H), 3.85 (s, 3H), 7.15(s, 1H), 7.65 (s, 1H).

Example 4

6-Methoxy-4-(3-methylbut-1-ynyl)pyridin-3-amine (Compound 4). To asolution of 4-iodo-6-methoxypyridin-3-amine (Compound 3, 845 mg, 3.4mmol) in Et₃N (12 ml) in a re-sealable pressure tube was addedPd(PPh₃)₂Cl₂ (24 mg, 0.034 mmol), CuI (7.0 mg, 0.034 mmol), and3-methyl-1-butyne (0.66 ml, 6.8 mmol). The mixture was stirred at roomtemperature for 20 h and the solvent was removed in vacuo. The residuewas purified by chromatography on silica gel (0→30% EtOAc-hexanes) toyield the title compound as beige solid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J=6.7 Hz, 6H), 2.76-2.93(m, 1H), 3.76 (s, 2H), 3.85 (s, 3H), 6.64 (s, 1H), 7.69 (s, 1H).

Example 5

2-Isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine (Compound 5). To asolution of 6-methoxy-4-(3-methylbut-1-ynyl)pyridin-3-amine (Compound 4,588 mg, 3.1 mmol) in N-methylpyrrolidone (10 ml) was added KOtBu (0.87g, 7.8 mmol) at room temperature. The mixture was heated to 140° C. for0.5 h and cooled to room temperature, quenched with H₂O, extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel (0→50% EtOAc-hexanes) to yield the title compound as lightbrown syrup.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (d, J=7.0 Hz, 6H), 2.97-3.16(m, 1H), 3.95 (s, 3H), 6.15 (m, 1H), 6.81 (m, 1H), 8.21 (s, 1H), 8.26(s, 1H).

Example 6

2-Isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (Compound6). POCl₃ (1.1 ml, 12.5 mmol) was added to anhydrous DMF (10 ml) at 0°C. slowly and stirred for 0.5 h. This was added to a solution of2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine (Compound 5, 468 mg, 2.5mmol) in anhydrous DMF (15 ml) at room temperature. The mixture was thenheated to 90° C. for 2 h and cooled to room temperature, quenchedcautiously with aqueous Na₂CO₃, extracted with EtOAc (×4). The combinedorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo. The residue was purified by chromatography on silica gel(0→100% EtOAc-hexanes) to yield the title compound as beige solid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.48 (d, J=7.0 Hz, 6H), 3.72-3.88(m, 1H), 3.98 (s, 3H), 7.52 (d, J=0.9 Hz, 1H), 8.35 (d, J=0.9 Hz, 1H),10.22 (s, 1H).

Example 7

1-Benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde(Compound 7). A mixture of2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde (Compound6, 110 mg, 0.50 mmol), benzyl bromide (0.18 ml, 1.50 mmol), and K₂CO₃(208 mg, 1.50 mmol) in DMF (2.5 ml) was stirred at room temperature for4 h. The solvent was removed in vacuo and the residue was purified bychromatography on silica gel (50% EtOAc-hexanes) to yield the titlecompound as yellow solid.

1H NMR (500 MHz, METHANOL-d₄) δ ppm 1.45 (d, J=7.3 Hz, 6H), 3.53-3.70(m, 1H), 3.92 (s, 3H), 5.62 (s, 2H), 7.06 (d, J=7.8 Hz, 2H), 7.21-7.39(m, 3H), 7.55 (s, 1H), 8.26 (s, 1H), 10.34 (s, 1H).

Example 8

1-Benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carboxylicacid (Compound 8). To a solution of1-benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carbaldehyde(Compound 7, 20 mg, 0.065 mmol) in t-BuOH (1.5 ml) and 2-methyl-2-butene(1 ml) was added a solution of NaH₂PO₄ (94 mg, 0.78 mmol) and NaClO₂(80%, 73 mg, 0.65 mmol) in H₂O (1.5 ml). The mixture was stirred at roomtemperature and additional 2-methyl-2-butene and a solution of NaH₂PO₄and NaClO₂ in H₂O were added at the above ratio every 6-16 h until theprogress of the reaction was satisfactory. The reaction mixture wasextracted with EtOAc (×3) and the combined organic layer was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by preparative thin layer chromatography (PTLC) on silica gel(50% EtOAc-hexanes) to yield the title compound.

1H NMR (300 MHz, METHANOL-d₄) δ ppm 1.39 (d, J=7.3 Hz, 6H), 3.90 (s,3H), 3.92-4.03 (m, 1H), 5.62 (s, 2H), 7.00 (dd, J=8.1, 1.3 Hz, 2H),7.20-7.37 (m, 3H), 7.43 (s, 1H), 8.15 (s, 1H).

Example 9

1-Benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carboxamide(Compound 9). To a solution of1-benzyl-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carboxylicacid (Compound 8, 6.0 mg, 0.019 mmol) and 3,4-difluorobenzylamine (7.0l, 0.057 mmol) in CH₂Cl₂ (1.0 ml) was added EDC (5.5 mg, 0.029 mmol),DMAP (3.5 mg, 0.029 mmol), and Et₃N (25 l). The mixture was stirred atroom temperature for 16 h and was directly purified by preparative thinlayer chromatography (PTLC) on silica gel (50% EtOAc-hexanes) to yieldthe title compound.

1H NMR (300 MHz, METHANOL-d₄) δ ppm 1.35 (d, J=7.0 Hz, 6H), 3.38-3.59(m, 1 H), 3.86 (s, 3H), 4.57 (s, 2H), 5.56 (s, 2H), 6.91 (s, 1H), 6.98(dd, J=7.9, 1.5 Hz, 2H), 7.17-7.41 (m, 6H), 8.14 (s, 1H).

Example 10

1-Benzyl-N-(3,4-difluorobenzyl)-5-hydroxy-2-isopropyl-1H-pyrrolo[2,3-c]pyridine-3-carboxamide(Compound 10). A solution of1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-5-methoxy-1H-pyrrolo[2,3-c]pyridine-3-carboxamide(Compound 9, 7.0 mg, 0.016 mmol) in HBr (48%, 0.5 ml) and HOAc (1.0 ml)was heated to 120° C. for 5 h. The solvent was removed in vacuo and theresidue was purified by preparative thin layer chromatography (PTLC) onsilica gel (10% MeOH—CH₂Cl₂) to yield the title compound.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.41 (d, J=7.0 Hz, 6H), 3.70-3.86(m, 1H), 4.58 (d, J=5.6 Hz, 2H), 5.28 (s, 2H), 6.33 (s, 1H), 6.64 (s,1H), 6.96 (d, J=7.3 Hz, 2H), 7.06-7.35 (m, 6H), 7.41 (s, 1H).

Example 11

2-Chloro-5-iodopyridin-4-amine (Compound 11). This compound was preparedaccording to the following literature procedure: Hu et al.; Bioorg. Med.Chem. Lett. 2006 16, 4567-4570.

Example 12

2-Chloro-5-(3-methylbut-1-ynyl)pyridin-4-amine (Compound 12). To asolution of 2-chloro-5-iodopyridin-4-amine (Compound 11, 2.55 g, 10.0mmol) in Et₃N (35 ml) was added Pd(PPh₃)₂Cl₂ (70 mg, 0.10 mmol), CuI (19mg, 0.10 mmol), and 3-methyl-1-butyne (1.2 ml, 12 mmol). The reactionwas stirred at room temperature for 20 h and was quenched with H₂O,extracted with EtOAc (×2). The combined organic layer was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by chromatography on silica gel (0→30% EtOAc-hexanes) to yieldthe title compound as an off-white solid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=6.7 Hz, 6H), 2.71-3.02(m, 1 H), 4.70 (s, 2H), 6.57 (s, 1H), 8.08 (s, 1H).

Example 13

1-Benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine (Compound 13).To a solution of 2-chloro-5-(3-methylbut-1-ynyl)pyridin-4-amine(Compound 12, 0.82 g, 4.2 mmol) in NMP (10 ml) was added KOtBu (2.40 g,21 mmol). The mixture was stirred at 160° C. for 6 h and was cooled toroom temperature, diluted with THF (10 ml) and DMF (15 ml). Benzylbromide (0.50 ml, 4.2 mmol) was added. The mixture was stirred at roomtemperature for 16 h and was quenched with H₂O, extracted with EtOAc(×2). The combined organic layer was washed with brine, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified bychromatography on silica gel (0→50% EtOAc-hexanes) to yield the titlecompound as a white solid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (d, J=7.0 Hz, 6H), 2.89-3.06(m, 1H), 5.31 (s, 2H), 6.42 (s, 1H), 6.86-6.94 (m, 2H), 7.07 (s, 1H),7.21-7.37 (m, 3H), 8.58 (s, 1H).

Example 14

1-Benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde(Compound 14). POCl₃ (0.31 ml, 3.42 mmol) was added to anhydrous DMF (5ml) at 0° C. slowly and stirred for 20 min. To this solution was added asolution of 1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine(Compound 13, 195 mg, 0.68 mmol) in anhydrous DMF (7 ml) at roomtemperature. The mixture was stirred at room temperature for 2 h and wasthen heated to 60° C. for 2 h and 80° C. for 0.5 h. The reaction wascooled to room temperature, quenched cautiously with aqueous Na₂CO₃,extracted with EtOAc (×2). The combined organic layer was washed withbrine, dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by chromatography on silica gel (0→30% EtOAc-hexanes) to yieldthe title compound.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.46 (d, J=7.3 Hz, 6H), 3.35-3.57(m, 1 H), 5.40 (s, 2H), 6.95 (dd, J=7.5, 2.2 Hz, 2H), 7.17 (s, 1H),7.29-7.41 (m, 3H), 9.33 (s, 1H), 10.46 (s, 1H).

Example 15

1-Benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylicacid (Compound 15). To a solution of1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde(Compound 14, 146 mg, 0.47 mmol) in t-BuOH (15 ml) and 2-methyl-2-butene(10 ml) was added a solution of NaH₂PO₄ (1.41 g, 11.8 mmol) and NaClO₂(80%, 1.05 g, 9.3 mmol) in H₂O (10 ml). The mixture was stirred at roomtemperature for 16 h and was extracted with EtOAc (×2). The combinedorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo. The residue was purified by chromatography on silica gel(0→100% EtOAc-hexanes, then 0→30% MeOH—CH₂Cl₂) to yield the titlecompound as a yellow solid.

1H NMR (300 MHz, DMSO-d₆) δ ppm 1.27 (d, J=7.0 Hz, 6H), 3.65-3.91 (m,1H), 5.67 (s, 2H), 6.85-7.03 (m, 2H), 7.19-7.43 (m, 3H), 7.71 (s, 1H),8.97 (s, 1H), 12.68 (s, 1H).

Example 16

1-Benzyl-6-chloro-N-(3,4-difluorobenzyl)-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carboxamide(Compound 16). To a solution of1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carboxylicacid (Compound 15, 138 mg, 0.42 mmol) and 3,4-difluorobenzylamine (0.15ml, 1.26 mmol) in DMF (4.0 ml) was added EDC (121 mg, 0.63 mmol) andDMAP (77 mg, 0.63 mmol). The mixture was stirred at room temperature for16 h and was diluted with EtOAc, washed with H₂O and brine, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified bychromatography on silica gel (0→100% EtOAc-hexanes) to yield the titlecompound as a light yellow solid.

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (d, J=7.0 Hz, 6H), 3.42-3.54(m, 1 H), 4.65 (d, J=6.2 Hz, 2H), 5.33 (s, 2H), 6.86 (dd, J=7.2, 2.2 Hz,2H), 6.97-6.99 (m, 1H), 7.01 (t, J=6.0 Hz, 1H), 7.09-7.17 (m, 2H),7.21-7.32 (m, 4H), 8.57 (s, 1H).

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. Thus, however detailed the foregoing may appearin text, it should not be construed as limiting the overall scopehereof; rather, the ambit of the present invention was to be governedonly by the lawful construction of the appended claims.

1. A compound having the formula:

wherein n is 2 and indicates the number of enchained nitrogen atoms inthe condensed 6 member ring; m is 0 or 1; R₁ is aryl, heteroaryl oralkyl; R₂ is selected from the group consisting of C₁₋₆ hydrocarbyl,alkylacyl and hydroxyalkyl; R₃ is selected from the group consisting ofaryl, heteroaryl, or alkyl; R₄ is H, OH, —O—(C₁₋₆ alkyl), —NH—(C₁₋₆alkyl), and oxide; R₅ is selected from the group consisting of H,halogen, C₁₋₆ alkyl, O—(C₁₋₆ alkyl), aryl, heteroaryl, —C(═O)(C₁₋₆alkyl), substituted and un-substituted oxazolin-2-yl; X is selected fromthe group consisting of O, NH, —C(═O)— and —N═CH—; and L is selectedfrom the group consisting of alkylene, and carbonyl.
 2. The compound ofclaim 1 wherein R1 is selected from the group consisting of phenyl,pyridine-2-yl, pyridine-3-yl, oxazol-2-yl, isoxazol-3-yl,5-methyl-isoxazol-3-yl and 3-methyl-isoxazol-5-yl and isopropyl.
 3. Thecompound of claim 1 wherein R2 is selected from the group consisting ofisopropyl, cyclobutyl, cyclopentyl, acetyl and 1-hydroxyethyl.
 4. Thecompound of claim 1 wherein R3 is selected from the group consisting of3,4-difluorophenyl, 3,5-difluorophenyl, 3-fluorophenyl, 4-fluorophenyl,3-fluoropyridine-5-yl, 3-nitrophenyl and phenyl.
 5. The compound ofclaim 1 wherein R4 is selected from the group consisting of hydrogen,hydroxyl, isobutoxyl and cyclopentyloxyl.
 6. The compound of claim 1wherein R₅ is selected from the group consisting of C₁-C₆ alkyl,thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,tetrahydrofuranyl, tetrahydropyranyl, C₁-C₆ alkoxyl, alkylacyl, andsubstituted or un-substituted oxazolin-2-yl.
 7. The compound of claim 1wherein X is selected from the group consisting of O, C(O) and NH. 8.The compound of claim 7 wherein R₅ is selected from the group consistingof propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclopentyl, thiazolyl, oxazolyl,oxadiazolyl, thiadiazolyl, pyridinyl, tetrahydrofuranyl,tetrahydropyranyl, C₁-C₆ alkoxyl, alkylacyl, and substituted orun-substituted oxazolin-2-yl.
 9. The compound of claim 1 having aformula: